DESCRIPTION OF OVERALL CENTER (provided by applicant): The Harvard Digestive Disease Center (HDDC) is a community of 61 independent investigators with over $34M (28% NIDDK) annual research funding and 21 Associate Members, all conducting research directly related to digestive diseases. HDDC members' research addresses the fundamental mechanisms that underlie normal digestive tract function and the pathogenesis of digestive disease, focusing on 4 Themes: Epithelial Cell, Developmental, and Stem Cell Biology; Innate and Adaptive Mucosal Immunology; Gut Infections and Microbiome; and Hepatic Cell Physiology and Metabolism. These research areas address the basis for intestinal and inflammatory bowel diseases; gut infections; effects of the gut microbiome on intestinal and systemic physiology and metabolism; and regenerative medicine of the intestine and liver. Members' resources and technical capabilities are amplified through services, equipment and training in 3 Biomedical Cores that provide (B) high-resolution microscopy & histopathology, (C) epithelial cell culture & mucosal cell analysis, and (D) gnotobiotic mice, microbiological and metabolic analyses. The HDDC Clinical Component supports clinical and translational GI research through HDDC-subsidized biostatistical and bio-repository services. The Center fosters scientific collaborations through an Enrichment Program organized by Themes, including an annual symposium, a biennial regional conference Frontiers in Mucosal Immunology, seminars, and workshops focused on young investigators. The HDDC also promotes training of young scientists through a competitive Pilot- Feasibility Grant Program that has supported 45 trainees in the past 8 years, with all but one still active in digestive diseases-related research. Center Directors Wayne Lencer (PI) and Associate Director Richard Blumberg (Co-PI) are Division Chiefs of Pediatric and Adult GI at two major Harvard teaching hospitals, and leaders of NIH-funded training programs in Gastroenterology. They are assisted by an Executive Committee that includes all Core Directors and Theme Leaders, and guided by an External Advisory Board of leaders in GI-related research. The HDDC's overarching mission is to foster and expand basic and translational science in digestive diseases by connecting people, creating opportunity, and extending resources.